Gammaherpesviruses are closely associated with the development of lympho-proliferative disease and lymphomas, as well as other cancers. Notably, herpesviruses in general are able to establish life-long infections in their natural host(s). The long term goal of this research is to understand how gamma-herpesviruses manipulate normal B cell development to persist within the lymphoid compartment of the infected host. Understanding the mechanisms used by gamma-herpesviruses to persist in the infected host may lead to the development of strategies for interfering with chronic infection. Such therapies would be useful in the management of immunosuppressed individuals (e.g., organ transplant and AIDS patients) who are particularly susceptible to developing gamma-herpesvirus-associated tumors. The focus of the proposed studies on murine gamma- herpesvirus 68 (MHV68) represents an ongoing effort to exploit this tractable small animal model to determine mechanism involved in the establishment and maintenance of ?-herpesvirus latency within the lymphoid compartment. The specific aims of this renewal application are as follows: Aim 1. Role of IL-21 in MHV68 B cell latency Aim 2. Characterize the early steps in the establishment of MHV68 latency in B cells Aim 3. Characterize the specificity of MHV68 latently infected B cell population